Project Summary There are currently no approved vaccines for most emerging biological pathogens (Ebola, Chikungunya, MERS CoV, SARS, Zika), opportunistic infections (S. aureus, Candidiasis, adenovirus) or potential bioterrorism agents (Y. pestis, B. Pseudomallei, F. tularensis, Bunyaviridae, Flaviviridae), and therapeutic interventions such as antibiotics and antivirals are only effective for a select few pathogens. A promising approach for rapidly neutralizing the risk of pathogen exposure is the use of immunomodulators capable of eliciting a robust innate immune response within hours of administration that would provide protective resistance against a wide range of infectious diseases. Proof-of-principle has been established that a new class of chemically and metabolically more stable synthetic TLR4 agonists provide safe and effective protection to mice when administered intranasally two days before a lethal influenza virus challenge. In this Phase II application, we will further optimize these new synthetic TLR4 agonists and formulations for stability, potency and safety, and optimize an administration schedule to provide weeks-long non-specific resistance against influenza virus. We will also assess the potential toxicity of the new TLR4 agonists in mice and develop a scalable cGMP synthesis of the lead candidate. This phase II proposal has the potential to develop a new broad-spectrum immunomodulator that would provide non-specific protective resistance (NSR) against a wide range of biological pathogens, and is primarily targeted for preventing upper respiratory tract infections in individuals or populations at risk for emerging or opportunistic pathogen exposure. Such treatment could reduce morbidity and mortality associated with seasonal or pandemic influenza viruses as well as other respiratory pathogens of significant medical concern. The work proposed herein will comprise the pre-clinical basis for IND-filing and human clinical trials using a safe and effective synthetic TLR4 agonist for individuals or populations with a high risk of exposure to seasonal and pandemic influenza viruses.